| Summary: | In the past, proinflammatory CD11b<sup>+</sup>Ly6C<sup>hi</sup> monocytes were predominantly considered as a uniform population. However, recent investigations suggests that this population is far more diverse than previously thought. For example, in mouse models of <i>Entamoeba (E.) histolytica</i> and <i>Listeria (L.) monocytogenes</i> liver infections, it was shown that their absence had opposite effects. In the former model, it ameliorated parasite-dependent liver injury, whereas in the listeria model it exacerbated liver pathology. Here, we analyzed Ly6C<sup>hi</sup> monocytes from the liver of both infection models at transcriptome, protein, and functional levels. Paralleled by <i>E. histolytica</i>- and <i>L. monocytogenes</i>-specific differences in recruitment-relevant chemokines, both infections induced accumulation of Ly6C<sup>+</sup> monocytes at infection sites. Transcriptomic analysis revealed a high similarity between monocytes from naïve and parasite-infected mice and a clear proinflammatory phenotype of listeria-induced monocytes. This was further reflected by the upregulation of M2-related transcription factors (e.g., <i>Mafb, Nr4a1, Fos</i>) and higher CD14 expression by Ly6C<sup>hi</sup> monocytes in the <i>E. histolytica</i> infection model. In contrast, monocytes from the listeria infection model expressed M1-related transcription factors (e.g., <i>Irf2, Mndal, Ifi204</i>) and showed higher expression of CD38, CD74, and CD86, as well as higher ROS production. Taken together, proinflammatory Ly6C<sup>hi</sup> monocytes vary considerably depending on the causative pathogen. By using markers identified in the study, Ly6C<sup>hi</sup> monocytes can be further subdivided into different populations.
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